Off-study utilization of experimental therapies: Analysis of GOG249-eligible cohorts using real world data.

OBJECTIVE: Adjuvant management of women with high-intermediate- and high-risk early-stage endometrial cancer remains controversial. Recently published results of GOG 249 revealed that vaginal brachytherapy plus chemotherapy (VBT + CT) was not superior to whole pelvic radiation therapy (WPRT) and was associated with more toxicities and higher nodal recurrences. This study examined off-study utilization of VBT + CT among women who met criteria for GOG 249 in the period prior to study publication. METHODS: Women diagnosed with FIGO IA-IIB endometrioid, serous, or clear cell uterine cancer between 2004-2015 and treated with hysterectomy and radiotherapy (RT) were identified in the National Cancer Database. Cochrane-Armitrage trend test was used to assess trends over time. Univariate and multivariate Cox analyses were performed to calculate odds ratio (OR) of VBT + CT receipt and hazard ratio (HR) of OS. Propensity-score matched analysis was conducted to account for baseline differences. RESULTS: 9956 women met inclusion criteria. 7548 women (75.8%) received WPRT while 2408 (24.2%) received VBT + CT in the study period. From 2004-2015, there was a significant increase in VBT + CT use (p < 0.001) with the largest overall increase occurring in 2009 to 22%. Factors significantly associated with VBT + CT receipt included higher socioeconomic status (p < 0.001), higher grade endometrioid cancer (p < 0.001), and aggressive histology (p < 0.001). After propensity-score matching, VBT + CT was associated with improved OS (HR 0.74, 95% CI 0.58-0.93); however, when stratified by FIGO stage, VBT + CT was only associated with improved OS for FIGO stage 1B (HR 0.62, 95% CI 0.44-0.87). CONCLUSIONS: There was significant use of experimental arm off-study treatment in the United States prior to report of GOG 249 results. Providers should be cautious when offering off-study treatment utilizing an experimental regimen given uncertainty about efficacy and toxicity.

Prospective analysis of Ki-67 as an independent predictor of oncologic outcomes in patients with high grade upper tract urothelial carcinoma.

PURPOSE: We determined the association of the proliferation marker Ki-67 with pathological parameters and oncologic outcomes in patients with high grade upper tract urothelial carcinoma. MATERIALS AND METHODS: Immunohistochemical staining for Ki-67 was done prospectively in 101 consecutive patients undergoing radical nephroureterectomy/ureterectomy for high grade upper tract urothelial carcinoma. Data were compared based on Ki-67 status (normal vs over expressed). Survival was assessed by the Kaplan-Meier method. Cox regression analysis was done to identify independent predictors of time dependent outcomes. RESULTS: Median patient age was 70.0 years and median followup was 22.0 months (range 1 to 77). Overall, 30.2% of the population experienced recurrence and 24.8% died of upper tract urothelial carcinoma. Organ confined disease (T2 or less and lymph node negative), lymphovascular invasion and sessile architecture were present in 56.3%, 33.3% and 20.8% of patients, respectively. Ki-67 was over expressed in 73.3% of patients and associated with adverse pathological features. Patients with over expressed Ki-67 had significantly worse recurrence-free survival (43.2 vs 69.0 months, p = 0.006) and cancer specific survival (48.9 vs 68.9 months, p = 0.031) than patients with normal Ki-67. Patients with nonmetastatic disease similarly had worse recurrence-free survival (40.7 vs 71.8 months, p = 0.003) and cancer specific survival (41 months vs not attained, p = 0.008) for over expressed vs normal Ki-67. After adjusting for the effects of organ vs nonorgan confined disease Ki-67 over expression was an independent predictor of recurrence-free survival in the total cohort (HR 4.3, p = 0.05) and in patients with nonmetastatic disease (HR 8.5, p = 0.038). CONCLUSIONS: Ki-67 over expression was associated with adverse pathological features in cases of upper tract urothelial carcinoma. It was also an independent predictor of recurrence-free survival in patients with high grade upper tract urothelial carcinoma.

Prediction model to estimate overall survival benefit of postoperative radiotherapy for resected major salivary gland cancers.

OBJECTIVES: To develop and validate a prediction model to estimate overall survival (OS) with and without postoperative radiotherapy (PORT) for resected major salivary gland (SG) cancers. MATERIALS AND METHODS: Adults in the National Cancer Database diagnosed with invasive non-metastatic major SG cancer between 2004 and 2015 were identified. Exclusion criteria included prior malignancy, pT1N0 or unknown stage, no or unknown surgery, and neoadjuvant therapy. Cox proportional hazards models evaluated the effect of covariates on OS. A multivariate regression model was utilized to predict 2-, 5-, and 10-year OS. Internal cross-validation was performed using 50-50 hold-out and Harrell's concordance index. RESULTS: 18,400 subjects met inclusion criteria, including 9,721 (53%) who received PORT. Distribution of SG involvement was 86% parotid, 13% submandibular, and 1% sublingual. Median follow-up for living subjects was 4.9 years. PORT was significantly associated with improved OS for the following subgroups by log-rank test: pT3 (p < 0.001), pT4 (p < 0.001), high grade (p < 0.001), node-positive (p < 0.001), and positive margin (p < 0.001). The following variables were incorporated into a multivariate model: age, sex, Charlson-Deyo comorbidity score, involved SG, pathologic T-stage, grade, margin status, ratio of nodal positivity, and PORT. The resulting model based on data from 6,138 subjects demonstrated good accuracy in predicting OS, with Harrell's concordance index of 0.73 (log-rank p < 0.001). CONCLUSION: This cross-validated prediction model estimates 2-, 5-, and 10-year differences in OS based on receipt of PORT for resected major SG cancers using readily available clinicopathologic features. Clinicians can utilize this tool to aid personalized adjuvant therapy decisions.

Nomogram Predicting Overall Survival Benefit of Stereotactic Ablative Radiotherapy for Early-Stage Non-Small Cell Lung Cancer.

OBJECTIVES: To develop and validate a nomogram that predicts overall survival (OS) for patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR) vs. observation. MATERIALS AND METHODS: Adults with biopsy-proven T1-T2N0 NCSLC treated with SABR (30-70 Gy in 1-10 fractions with biologically effective dose ≥100 Gy10) or observation between 2004 and 2015 in the National Cancer Database (NCDB) were identified. Propensity score was used to match SABR and observation cohorts on prognostic demographic and clinicopathologic factors identified by logistic regression. Using backward selection, a multivariable Cox proportional hazard was identified predicting 2- and 5-year OS via a nomogram. Model prediction accuracy was assessed by time-dependent receiver operating characteristic (ROC) curves and integrated area under the ROC curve (AUC) analysis. RESULTS: A total of 22,073 adults met inclusion criteria and 4418 matched pairs (total n = 8836) were identified for nomogram development. The factors most strongly associated with improved OS on multivariable analysis included younger age (HR 0.82 by decade, P < .001), female sex (HR 0.81, P < .001), lower comorbidity index (HR 0.65 for 0 vs. ≥3, P < .001), smaller tumor size (HR 0.60 for ≤3 cm vs. 5.1-7 cm, P < .001), adenocarcinoma histology (P < .001), and receipt of SABR (P < .001). Interaction between SABR and histology was significantly associated with OS (P = .017). Relative to adenocarcinoma, patients with squamous cell carcinoma who were observed (HR 1.44, 95% CI 1.33-1.56) or treated with SABR (HR 1.24, 95% CI 1.14-1.35) had significantly worse OS. The nomogram demonstrated fair accuracy for predicting OS, with an integrated time-dependent AUC of 0.694 over the entire follow-up period. CONCLUSION: This nomogram estimates OS at 2 and 5 years based on whether medically inoperable early-stage NSCLC patients receive SABR or elect for observation. Incorporation of other variables not captured within the NCDB may improve the model accuracy.

Comparing Outcomes of Oligometastases Treated with Hypofractionated Image-Guided Radiotherapy (HIGRT) with a Simultaneous Integrated Boost (SIB) Technique versus Metastasis Alone: A Multi-Institutional Analysis.

PURPOSE: We previously reported on the clinical outcomes of treating oligometastases with radiation using an elective simultaneous integrated boost technique (SIB), delivering higher doses to known metastases and reduced doses to adjacent bone or nodal basins. Here we compare outcomes of oligometastases receiving radiation targeting metastases alone (MA) versus those treated via an SIB. METHODS: Oligometastatic patients with ≤5 active metastases treated with either SIB or MA radiation at two institutions from 2013 to 2019 were analyzed retrospectively for treatment-related toxicity, pain control, and recurrence patterns. Tumor metastasis control (TMC) was defined as an absence of progression in the high dose planning target volume (PTV). Marginal recurrence (MR) was defined as recurrence outside the elective PTV but within the adjacent bone or nodal basin. Distant recurrence (DR) was defined as any recurrence that is not within the PTV or surrounding bone or nodal basin. The outcome rates were estimated using the Kaplan-Meier method and compared between the two techniques using the log-rank test. RESULTS: 101 patients were treated via an SIB to 90 sites (58% nodal and 42% osseous) and via MA radiation to 46 sites (22% nodal and 78% osseous). The median follow-up among surviving patients was 24.6 months (range 1.4-71.0). Of the patients treated to MA, the doses ranged from 18 Gy in one fraction (22%) to 50 Gy in 10 fractions (50%). Most patients treated with an SIB received 50 Gy to the treated metastases and 30 Gy to the elective PTV in 10 fractions (88%). No acute grade ≥3 toxicities occurred in either cohort. Late grade ≥3 toxicity occurred in 3 SIB patients (vocal cord paralysis and two vertebral body compression), all related to the high dose PTV and not the elective volume. There was similar crude pain relief between cohorts. The MR-free survival rate at 2 years was 87% (95% CI: 70%, 95%) in the MA group and 98% (95% CI: 87%, 99%) in the SIB group (p = 0.07). The crude TMC was 89% (41/46) in the MA group and 94% (85/90) in the SIB group. There were no significant differences in DR-free survival (65% (95% CI: 55-74%; p = 0.24)), disease-free survival (60% (95% CI: 40-75%; p = 0.40)), or overall survival (88% (95% CI: 73-95%; p = 0.26)), between the MA and SIB cohorts. CONCLUSION: Both SIB and MA irradiation of oligometastases achieved high rates of TMC and similar pain control, with a trend towards improved MR-free survival for oligometastases treated with an SIB. Further investigation of this technique with prospective trials is warranted.

Postoperative radiotherapy is associated with improved overall survival for alveolar ridge squamous cell carcinoma with adverse pathologic features.

BACKGROUND: Alveolar ridge squamous cell carcinoma (ARSCC) is poorly represented in randomized trials. METHODS: Adults in the National Cancer Database diagnosed with ARSCC between 2010 and 2014 who should be considered for postoperative radiotherapy (PORT) based on National Comprehensive Cancer Network (NCCN)-defined risk factors were identified. RESULTS: Eight hundred forty-five (58%) of 1457 patients meeting the inclusion criteria received PORT. PORT was associated with improved overall survival (OS) on unadjusted (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70-0.98, P = .02) and multivariable (HR 0.78, 95% CI 0.64-0.94, P = .002) analyses. PORT was associated with significantly improved 5-year OS for patients with 1 (68% vs 58%, P < .001), 2 (52% vs 31%, P < .001), and ≥3 (38% vs 24%, P < .001) NCCN-defined risk factors. Prognostic variables significantly associated with worse OS on multivariable analysis included advanced age, primary tumor size ≥3 cm, high grade, positive margin(s), stage N2-3, level IV/V nodal metastasis, and extranodal extension. CONCLUSION: PORT for resected ARSCC with adverse pathologic features is associated with significantly improved OS.

Radiogenomic Analysis of Locally Advanced Lung Cancer Based on CT Imaging and Intratreatment Changes in Cell-Free DNA.

The radiologic appearance of locally advanced lung cancer may be linked to molecular changes of the disease during treatment, but characteristics of this phenomenon are poorly understood. Radiomics, liquid biopsy of cell-free DNA (cfDNA), and next-generation sequencing of circulating tumor DNA (ctDNA) encode tumor-specific radiogenomic expression patterns that can be probed to study this problem. Preliminary findings are reported from a radiogenomic analysis of CT imaging, cfDNA, and ctDNA in 24 patients (median age, 64 years; range, 49-74 years) with stage III lung cancer undergoing chemoradiation on a prospective pilot study (NCT00921739) between September 2009 and September 2014. Unsupervised clustering of radiomic signatures resulted in two clusters that were associated with ctDNA TP53 mutations (P = .03) and changes in cfDNA concentration after 2 weeks of chemoradiation (P = .02). The radiomic features dissimilarity (hazard ratio [HR] = 0.56; P = .05), joint entropy (HR = 0.56; P = .04), sum entropy (HR = 0.53; P = .02), and normalized inverse difference (HR = 1.77; P = .05) were associated with overall survival. These results suggest heterogeneous and low-attenuating disease without a detectable ctDNA TP53 mutation was associated with early surges of cfDNA concentration in response to therapy and a generally better prognosis. Keywords: CT-Quantitative, Radiation Therapy, Lung, Computer Applications-3D, Oncology, Tumor Response, Outcomes Analysis Clinical trial registration no. NCT00921739 Supplemental material is available for this article. © RSNA, 2021.

Synergy between early-incorporation immunotherapy and extracranial radiotherapy in metastatic non-small cell lung cancer.

BACKGROUND: Combining radiotherapy (RT) and immunotherapy (IT) may enhance outcomes for metastatic non-small cell lung cancer (mNSCLC). However, data on the immunomodulatory effects of extracranial RT remains limited. This retrospective database analysis examined real-world practice patterns, predictors of survival, and comparative effectiveness of extracranial radioimmunotherapy (RT + IT) versus early-incorporation immunotherapy (eIT) in patients with mNSCLC. METHODS: Patients diagnosed with mNSCLC between 2004-2016 treated with eIT or RT + IT were identified in the National Cancer Database. Practice patterns were assessed using Cochrane-Armitrage trend test. Cox proportional hazards and Kaplan-Meier method were used to analyze overall survival (OS). Propensity score matching was performed to account for baseline imbalances. Biologically effective doses (BED) were stratified based on the median (39 Gy10). Stereotactic body radiotherapy (SBRT) was defined as above median BED in ≤5 fractions. RESULTS: eIT utilization increased from 0.3% in 2010 to 13.2% in 2016 (P<0.0001). Rates of RT + eIT increased from 38.8% in 2010 to 49.1% in 2016 among those who received eIT (P<0.0001). Compared to eIT alone, RT + eIT demonstrated worse median OS (11.2 vs. 13.2 months) while SBRT + eIT demonstrated improved median OS (25 vs. 13.2 months) (P<0.0001). There were no significant differences in OS based on sequencing of eIT relative to RT (log-rank P=0.4415) or irradiated site (log-rank P=0.1606). On multivariate analysis, factors associated with improved OS included chemotherapy (HR 0.86, P=0.0058), treatment at academic facilities (HR 0.83, P<0.0001), and SBRT (HR 0.60, P=0.0009); after propensity-score multivariate analysis, SBRT alone showed improved OS (HR 0.28, P<0.0001). CONCLUSIONS: Utilization of RT + eIT in mNSCLC is increasing. SBRT + eIT was associated with improved OS on propensity-score matched analysis. There were no significant differences in OS based on RT + eIT sequencing or site irradiated. Whether these observations reflect patient selection or possible immunomodulatory benefits of RT is unclear and warrants further study.

A design process for a 3D printed patient-specific applicator for HDR brachytherapy of the orbit.

BACKGROUND: This report describes a process for designing a 3D printed patient-specific applicator for HDR brachytherapy of the orbit. CASE PRESENTATION: A 34-year-old man with recurrent melanoma of the orbit was referred for consideration of re-irradiation. An applicator for HDR brachytherapy was designed based on the computed tomography (CT) of patient anatomy. The body contour was used to generate an applicator with a flush fit against the patient's skin while the planning target volume (PTV) was used to devise channels that allow for access and coverage of the tumor bed. An end-to-end dosimetric test was devised to determine feasibility for clinical use. The applicator was designed to conform to the volume and contours inside the orbital cavity. Support wings placed flush with the patient skin provided stability and reproducibility, while 16 source channels of varying length were needed for sufficient access to the target. A solid sheath, printed as an outer support-wall for each channel, prevented bending or accidental puncturing of the surface of the applicator. CONCLUSIONS: Quality assurance tests demonstrated feasibility for clinical use. Our experience with available 3D printing technology used to generate an applicator for the orbit may provide guidance for how materials of suitable biomechanical and radiation properties can be used in brachytherapy.

Evaluating treatment protocols for rectal squamous cell carcinomas: the Duke experience and literature.

BACKGROUND: Colorectal cancer is the third most common cancer in the United States and associated with significant morbidity and mortality. Within colorectal cancer histologies, squamous cell carcinomas (SCC) are rare compared to adenocarcinomas, with only about 200 cases reported to date. Because rectal SCC is rarely encountered, there is a lack of literature and clinical consensus surrounding its optimal treatment approach. Staging and management of SCC can be partly analogous to both rectal adenocarcinoma and anal canal SCC, which leads to a dilemma in how to best approach these patients. As large randomized prospective trials are unrealistic in the setting of this rare malignancy, this study evaluates an institutional experience and reviews the existing literature to help guide future management approaches. METHODS: This retrospective study compared various treatment regimens for rectal SCC patients treated at Duke University Medical Center from January 1, 1980 through December 31, 2016. Patients ≥18 years old with histologically confirmed, nonmetastatic rectal SCC were included. Due to small sample size, all statistical analyses were descriptive. For our systematic review, a comprehensive search of PubMed from 1933 to March 2018 was performed, with selected articles referenced to ensure all relevant publications were included. A qualitative analysis was performed to examine patient diagnoses, treatments, and disease- and treatment-related outcomes. RESULTS: Eight patients were included. Three patients underwent initial, curative attempt surgery and two of these patients required colostomy. With follow-up ranging from 7.1 to 31.5 months, one patient was alive with no evidence of disease while two developed local/regional recurrences. Five patients received definitive chemoradiation. Of these, three patients developed local/regional and/or metastatic recurrence. Two patients achieved complete response on imaging and currently remain disease-free (follow-up of 31.5 and 33.6 months). CONCLUSIONS: Although the review of our institutional experience is limited by small numbers, our analysis suggests that definitive chemoradiation therapy is the preferred treatment approach to rectal SCC based on improved disease-related outcomes, sphincter preservation and morbidity profiles. This conclusion is supported by a systematic literature review.

Multi-Institutional Analysis of Synchronous Prostate and Rectosigmoid Cancers.

Purpose: To perform a multi-institutional analysis of patients with synchronous prostate and rectosigmoid cancers. Materials and Methods: A retrospective review of Duke University and Durham Veterans Affairs Medical Center records was performed for men with both prostate and rectosigmoid adenocarcinomas from 1988 to 2017. Synchronous presentation was defined as symptoms, diagnosis, or treatment of both cancers within 12 months of each other. The primary study endpoint was overall survival. Univariate and multivariable Cox regression was performed. Results: Among 31,883 men with prostate cancer, 330 (1%) also had rectosigmoid cancer and 54 (16%) of these were synchronous. Prostate cancer was more commonly the initial diagnosis (59%). Fifteen (28%) underwent prostatectomy or radiotherapy before an established diagnosis of rectosigmoid cancer. Stage I, II-III, or IV rectosigmoid cancer was present in 26, 57, and 17% of men, respectively. At a median follow-up of 43 months, there were 18 deaths due rectosigmoid cancer and two deaths due to prostate cancer. Crude late grade ≥3 toxicities include nine (17%) gastrointestinal and six (11%) genitourinary. Two anastomotic leaks following low anterior resection occurred in men who received a neoadjuvant radiotherapy prostate dose of 70.6-76.4 Gy. Rectosigmoid cancer stages II-III (HR 4.3, p = 0.02) and IV (HR 16, p < 0.01) as well as stage IV prostate cancer (HR 31, p < 0.01) were associated with overall survival on multivariable analysis. Conclusions: Synchronous rectosigmoid cancer is a greater contributor to mortality than prostate cancer. Men aged ≥45 with localized prostate cancer should undergo colorectal cancer screening prior to treatment to evaluate for synchronous rectosigmoid cancer.

Radiation Therapy Practice Patterns for Brain Metastases in the United States in the Stereotactic Radiosurgery Era.

PURPOSE: Utilization of stereotactic radiosurgery (SRS) for brain metastases (BM) has increased, prompting reassessment of whole brain radiation therapy (WBRT). A pattern of care analysis of SRS and WBRT dose-fractionations was performed in patients presenting with BM at the time of cancer diagnosis. METHODS AND MATERIALS: Adults with BM at cancer diagnosis between 2010 to 2015 and no prior malignancy were identified in the National Cancer Database. SRS was defined using published thresholds. Short (ShWBRT), standard (StWBRT), and extended (ExWBRT) dose-fractionations were defined as 4 to 9, 10 to 15, and >15 fractions. Radioresistant histology was defined as melanoma, renal cell carcinoma, sarcoma or spindle cell, or gastrointestinal primary. RESULTS: Of 4,087,967 adults with their first lifetime cancer, 90,388 (2.2%) had BM at initial diagnosis. Of these, 11,486 (12.7%) received SRS and 24,262 (26.8%) WBRT as first-course radiation therapy. The proportion of annual WBRT use decreased from 27.8% to 23.5% of newly diagnosed patients, and SRS increased from 8.7% to 17.9%. Common dose-fractionations were 30 Gy in 10 fractions (56.8%) for WBRT and 20 Gy in 1 fraction (13.0%) for SRS. On multivariate analysis, factors significantly associated with SRS versus WBRT included later year of diagnosis (2015 vs 2010, adjusted odds ratio [aOR] = 2.4), radioresistance (aOR = 2.0), academic facility (aOR = 1.9), highest income quartile (aOR = 1.6), chemotherapy administration (aOR = 1.4), and longer travel distance (>15 vs < 5 miles, aOR = 1.4). Linear regression revealed significant ExWBRT reductions (-22.4%/y, R2 = 0.97, P < .001) and no significant change for ShWBRT or StWBRT. Patients were significantly more likely to receive ShWBRT than StWBRT if not treated with chemotherapy (aOR = 3.5). CONCLUSIONS: Utilization of WBRT, particularly ExWBRT, decreased while SRS utilization doubled as the first radiation therapy course in patients with BM at diagnosis. Patients with radioresistant histologies were more likely to receive SRS. Those not receiving chemotherapy, potentially owing to poor performance status, were less likely to receive SRS and more likely to receive ShWBRT.

Definitive Radiotherapy for Inoperable Stage IIB Non-small-cell Lung Cancer: Patterns of Care and Comparative Effectiveness.

BACKGROUND: The purpose of this study was to analyze practice patterns and perform comparative effectiveness of definitive radiotherapy techniques for inoperable stage IIB (American Joint Committee on Cancer eighth edition) non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Adults in the National Cancer Database diagnosed with T3N0M0 or T1-2N1M0 NCSLC between 2004 and 2015 who received definitive radiotherapy were identified. Cases were divided as stereotactic body radiotherapy (SBRT), hypofractionated radiotherapy (HFRT), or conventionally fractionated radiotherapy (CFRT) and stratified by systemic therapy (ST). Cox proportional hazards models evaluated the effect of covariates on overall survival (OS). Subgroup analysis by tumor size, chest wall invasion, multifocality, and ST use was performed with Kaplan-Meier estimates of OS. RESULTS: A total of 10,081 subjects met inclusion criteria: 4401 T3N0M0 (66.5% CFRT, 11.0% HFRT, and 22.5% SBRT) and 5680 T1-2N1M0 (92.5% CFRT and 7.5% HFRT). For T3N0M0 NSCLC, SBRT utilization increased from 3.7% in 2006% to 35.4% in 2015. Subjects treated with SBRT were more likely to have smaller tumors, multifocal tumors, or adenocarcinoma histology. SBRT resulted in similar or superior OS compared with CFRT for tumors > 5 cm, tumors invading the chest wall, or multifocal tumors. SBRT was significantly associated with improved OS on multivariate analysis (hazard ratio, 0.715; P < .001). For T1-2N1M0 NSCLC, patients treated with HFRT were significantly older and less likely to receive ST; nevertheless, there was no difference in OS between HFRT and CFRT on multivariate analysis. CONCLUSION: CFRT + ST is utilized most frequently to treat stage IIB NSCLC in the United States when surgery is not performed, though it is decreasing. SBRT utilization for T3N0M0 NSCLC is increasing and was associated with improved OS.

Changes on Midchemoradiation Therapy Fluorodeoxyglucose Positron Emission Tomography for Cervical Cancer Are Associated with Prognosis.

PURPOSE: To assess whether radiographic and metabolic changes on midchemoradiation therapy (CRT) fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) for cervical cancer predict outcome. METHODS AND MATERIALS: Women with International Federation of Gynecology and Obstetrics stage IB1-IVB cervical cancer treated with concurrent cisplatin-based CRT and brachytherapy were enrolled on a single-institution prospective clinical trial; FDG-PET/CT was obtained before CRT and at 30 to 36 Gy. Max and mean standard uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) for the primary tumor and clinically involved lymph nodes from the pre-CRT and intra-CRT FDG-PET/CT were recorded. Clinical endpoints analyzed include overall survival (OS), disease-free survival (DFS), and rates of cervical recurrence (CR), nodal recurrence (NR), and distant metastasis (DM). FDG-PET/CT variables and other prognostic factors associated with clinical endpoints were identified via univariate Cox proportional hazards modeling and competing risk analysis. RESULTS: Thirty women were enrolled from 2012 to 2016. After a median follow-up of 24 months, 2-year rates of OS, DFS, DM, NR, and CR were 68% (95% confidence interval [CI], 51%-85%), 44% (95% CI, 26%-63%), 42% (95% CI, 23%-59%), 14% (95% CI, 4%-30%), and 10% (95% CI, 2%-24%), respectively. Intra-PET metrics and TLG across all PET scans were most consistently associated with OS, DFS, DM, and NR on univariate analysis. Intra-CRT TLG was associated with OS (hazard ratio [HR] 1.35; 95% CI, 1.15-1.55; P = .001), DFS (HR 1.19; 95% CI, 1.04-1.34; P = .018), and NR (HR 1.25; 95% CI, 1.10-1.40; P = .002). No absolute or relative changes between parameters of baseline and mid-CRT FDG-PET/CT were associated with disease outcomes on univariate analysis, with the exception of relative change in mean standard uptake values and CR (P = .004). CONCLUSIONS: In this group of patients with high-risk cervical cancer treated with CRT and brachytherapy, TLG and metabolic tumor volume on intra-CRT FDG-PET/CT was associated with OS. These metrics may provide an early signal for selective treatment intensification with either dose escalation or adjuvant chemotherapy.

Radiation Records in the National Cancer Database: Variations in Coding and/or Practice Can Significantly Alter Survival Results.

PURPOSE: The aim of the current work was to quantify internally inconsistent and anomalous radiation therapy (RT) data in the National Cancer Database (NCDB) and determine their association with overall survival (OS) using node-positive uterine cancer as a test clinical scenario. MATERIALS AND METHODS: We identified all NCDB participants with International Federation of Gynecology and Obstetrics stage IIIC1 to IIIC2 uterine cancer treated with hysterectomy and adjuvant RT between 1998 and 2012. Variables that were reviewed to identify anomalous data included RT site, modality, dose, fractions, timing, duration, and stage. We used χ2 testing to associate anomalous data with reporting facility and demographic variables. OS was estimated using the Kaplan-Meier method and comparison between cohorts was performed using the log-rank test. Univariable and multivariable Cox proportional hazards regression analyses were performed. RESULTS: Of the 14,298 analyzed participants, 2,288 (16.0%) had one or more anomalous data entry, 538 (3.8%) likely because of an incomplete RT course. χ2 testing suggested differences in anomalous data prevalence by reporting facility type (P = .0007), geographic region (P < .001), distance from participants' homes (P < .001), diagnosis year (P < .001), and location of RT relative to reporting facility (P = .0038). Five-year OS in those with one or more anomalous data entry was 51.3% versus 58.0% for those without anomalous data (P < .001), and anomalous data remained significantly associated with OS on multivariable analysis. After excluding insufficient, excessive, or unknown total RT dose, anomalous data were no longer significant on multivariable analysis. CONCLUSION: The overwhelming majority of RT data within the NCDB seem to be appropriate for the clinical scenario. Nevertheless, approximately one eighth of participants in this test clinical scenario had adjuvant RT data that were internally inconsistent or outside generously defined norms. The presence of anomalous RT data was significantly associated with compromised OS, an effect not observed after correcting for total RT dose.

Hypofractionated Image-Guided Radiation Therapy With Simultaneous-Integrated Boost Technique for Limited Metastases: A Multi-Institutional Analysis.

Purpose: To perform a multi-institutional analysis following treatment of limited osseous and/or nodal metastases in patients using a novel hypofractionated image-guided radiotherapy with simultaneous-integrated boost (HIGRT-SIB) technique. Methods: Consecutive patients treated with HIGRT-SIB for ≤5 active metastases at Duke University Medical Center or Durham Veterans' Affairs Medical Center between 2013 and 2018 were analyzed to determine toxicities and recurrence patterns following treatment. Most patients received 50 Gy to the PTVboost and 30 Gy to the PTVelect simultaneously in 10 fractions. High-dose treatment volume recurrence (HDTVR) and low-dose treatment volume recurrence (LDTVR) were defined as recurrences within PTVboost and PTVelect, respectively. Marginal recurrence (MR) was defined as recurrence outside PTVelect, but within the adjacent bone or nodal chain. Distant recurrence (DR) was defined as recurrences not meeting HDTVR, LDTVR, or MR criteria. Freedom from pain recurrence (FFPR) was calculated in patients with painful osseous metastases prior to HIGRT-SIB. Outcome rates were estimated at 12 months using the Kaplan-Meier method. Results: Forty-two patients met inclusion criteria with 59 sites treated with HIGRT-SIB (53% nodal and 47% osseous). Median time from diagnosis to first metastasis was 31 months and the median age at HIGRT-SIB was 69 years. The most common primary tumors were prostate (36%), gastrointestinal (24%), and lung (24%). Median follow-up was 11 months. One acute grade ≥3 toxicity (febrile neutropenia) occurred after docetaxel administration immediately following HIGRT-SIB. Four patients developed late grade ≥3 toxicities: two ipsilateral vocal cord paralyzes and two vertebral compression fractures. The overall pain response rate was 94% and the estimated FFPR at 12 months was 72%. The estimated 12 month rate of HDTVR, LDTVR, MR, and DR was 3.6, 6.2, 7.6, and 55.8%, respectively. DR preceded MR, HDTVR, or LDTVR in each instance. The estimated 12 month probability of in-field and marginal control was 90.0%. Conclusion: Targeting areas at high-risk for occult disease with a lower radiation dose, while simultaneously boosting gross disease with HIGRT in patients with limited osseous and/or nodal metastases, has a high rate of treated metastasis control, a low rate of MR, acceptable toxicity, and high rate of pain palliation. Further investigation with prospective trials is warranted.

Dynamic Changes in Circulating Tumor DNA During Chemoradiation for Locally Advanced Lung Cancer.

PURPOSE: Concurrent chemoradiation therapy (CRT) is the principal treatment modality for locally advanced lung cancer. Cell death due to CRT leads to the release of cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) into the bloodstream, but the kinetics and characteristics of this process are poorly understood. We hypothesized that there could be clinically meaningful changes in cfDNA and ctDNA during a course of CRT for lung cancer. METHODS AND MATERIALS: Multiple samples of plasma were obtained from 24 patients treated with CRT for locally advanced lung cancer to a mean dose of 66 Gy (range, 58-74 Gy) at the following intervals: before CRT, at weeks 2 and 5 during CRT, and 6 weeks after treatment. cfDNA was quantified, and a novel next generation sequencing (NGS) technique using enhanced tagged/targeted-amplicon sequencing was performed to analyze ctDNA. RESULTS: Patients for whom specific mutations in ctDNA were undetectable at the baseline time point had improved survival, and potentially etiologic driver mutations could be tracked throughout the course of CRT via NGS in multiple patients. We quantified the levels of cfDNA from patients before CRT, at week 2, week 5, and at 6 weeks after treatment. No differences were observed at weeks 2 and 5 of therapy, but we noted a significant increase in cfDNA in the posttreatment follow-up samples compared with samples collected before CRT (P = .05). CONCLUSIONS: Dynamic changes in both cfDNA and ctDNA were observed throughout the course of CRT in patients with locally advanced lung cancer. Specific mutations with therapeutic implications can be identified and tracked using NGS methodologies. Further work is required to characterize the changes in cfDNA and ctDNA over time in patients treated with CRT and to assess the predictive and prognostic potential of this powerful technology.

Early Results of Lung Cancer Screening and Radiation Dose Assessment by Low-dose CT at a Community Hospital.

BACKGROUND: The National Lung Screening Trial showed a reduction in overall and cancer-specific mortality for patients screened with low-dose computed tomography (LDCT) versus chest radiograph. Some question whether this can be achieved in community healthcare settings. Our aim was to analyze lung cancer screening outcomes and administered radiation dose using LDCT scans at a community hospital. PATIENTS AND METHODS: We retrospectively reviewed the records of 680 patients who underwent LDCT between June 2014 and December 2015, and who met Centers for Medicare and Medicaid Services lung cancer screening criteria: asymptomatic, aged 55 to 77 years, smoked within the last 15 years, and ≥ 30 pack-year history. Effective and absorbed doses were calculated and correlated with gender and body mass index. RESULTS: Among the 133 patients (19.6%) with a positive screening result (Lung Imaging Reporting and Data System score of 3 or 4), 18 lung cancers were identified in 16 patients, 56.3% (9 of 16) of which were stage I non-small-cell lung cancer. The false-positive rate was 82.8% (95% confidence interval, 73.6%-89.8%). Mean estimated effective dose using dose length product and size-specific dose estimate using water equivalent diameter were 1.2 mSv and 3.7 mGy for women and 1.4 mSv and 3.9 mGy for men, respectively. All dosing metrics were strongly correlated with body mass index (P < .0001). CONCLUSIONS: Over half of screening patients diagnosed with non-small-cell lung cancer in our community had stage I disease, which we anticipate translating into significantly improved mortality. Patient radiation dose from LDCT scans is approximately one-fifth that from standard CT chest examinations.

Pretreatment biopsy analysis of DAB2IP identifies subpopulation of high-risk prostate cancer patients with worse survival following radiation therapy.

Decreased expression of tumor suppressor DAB2IP is linked to aggressive cancer and radiation resistance in several malignancies, but clinical survival data is largely unknown. We hypothesized that pretreatment DAB2IP reduction would predict worse prostate cancer-specific survival (PCSS). Immunohistochemistry of pretreatment biopsies was scored by an expert genitourinary pathologist. Other endpoints analyzed include freedom from biochemical failure (FFBF), castration resistance-free survival (CRFS), and distant metastasis-free survival (DMFS). Seventy-nine patients with NCCN-defined high-risk prostate cancer treated with radiotherapy from 2005 to 2012 at our institution were evaluated. Twenty-eight percent (22/79) of pretreatment biopsies revealed DAB2IP-reduction. The median follow up times were 4.8 years and 5.3 years for patients in the DAB2IP-reduced group and DAB2IP-retained group, respectively. Patients with reduced DAB2IP demonstrated worse outcome compared to patients retaining DAB2IP, including FFBF (4-year: 34 vs. 92%; P < 0.0001), CRFS (4-year: 58 vs. 96%; P = 0.0039), DMFS (4-year: 58 vs. 100%; P = 0.0006), and PCSS (5-year: 83 vs. 100%; P = 0.0102). Univariate analysis showed T stage, N stage, and Gleason score were statistically significant variables. Pretreatment tumor DAB2IP status remained significant in multivariable analyses. This study suggests that about one-fourth of men with high-risk prostate cancer have decreased tumor expression of DAB2IP. This subpopulation with reduced DAB2IP has a suboptimal response and worse malignancy-specific survival following radiation therapy and androgen deprivation. DAB2IP loss may be a genetic explanation for the observed differences in aggressive tumor characteristics and radiation resistance. Further study into improving treatment response and survival in this subpopulation is warranted.